The interaction between the stress axis and endogenous opioid systems has gained substantial clinical interest as it is increasingly recognized that stress predisposes to opiate abuse. For example, stress has been implicated as a risk factor in vulnerability to the initiation and maintenance of opiate abuse and is thought to play an important role in relapse in subjects with a history of abuse. However, the impact of stress-opioid interactions extends beyond vulnerability to opiate abuse. Numerous reports indicating that stress alters individual sensitivity to opiates suggest that prior stress can influence the pharmacodynamics of opiates that are used in clinical settings. Conversely, the effects of opiates on different components of the stress axis can impact on individual responsivity to stressors and potentially predispose individuals to stress- related psychiatric disorders. Because these interactions have potentially widespread clinical consequences, it is important to identify substrates of the stress response and endogenous opioid systems that interact and the specific points at which stress circuits and endogenous opioid systems intersect. During the previous funding period, we generated anatomical and physiological evidence that the locus coeruleus (LC)-norepinephrine (NE) system is reciprocally regulated by endogenous opioids and corticotropin-releasing factor (CRF). It was also demonstrated that chronic morphine sensitized the LC-NE system to CRF and stress, providing a potential mechanism that could link opiate use and vulnerability to stress-related psychiatric disorders. Importantly, new evidence was obtained for novel presynaptic actions of kappa-opioids on LC afferents, thus adding another dimension to our model of how this central NE system is co-regulated by opioids and CRF. Our general goals in this competing renewal application are to 1) identify neuroanatomical substrates for glutamate-opioid and CRF-opioid interactions that impact on the function of the LC-NE system, 2) characterize kappa-opioid receptor mediated regulation of LC spontaneous activity and afferent evoked activity, 3) characterize the impact of kappa-opioid receptor modulation of the LC on forebrain NE efflux and a behavioral endpoint of attention. This research will enhance our understanding of the interactions between stress and drug abuse and contribute to improving public health.